RU2006143842A - NEW SUBSTITUTED THIOPHENCARBOXAMIDES, THEIR PRODUCTION AND USE thereof AS MEDICINES - Google Patents

Claims (15)

1. Substituted thiophene-2-carboxamides of the general formula

, characterized in that A represents the remainder of the General formula

,

,

,

,

,

,

,

,

,

,

,

or

where m denotes the number 1 or 2, R ^8a in each case independently represents a hydrogen or halogen atom, C ₁ -C ₅ alkyl, hydroxy group, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy group, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl , amino group, C ₁ -C ₅ alkylamino group, di- (C ₁ -C ₅ alkyl) amino group, amino-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkylamino-C ₁ -C ₅ alkyl, di- (C ₁ -C ₅ alkyl) amino-C ₁ -C ₅ alkyl, aminocarbonyl, C ₁ -C ₅ alkylaminocarbonyl, di- (C ₁ -C ₅ alkyl) aminocarbonyl or a C ₁ -C ₅ alkylcarbonylamino group, while in the above substituted 5-7 membered residues A, the heteroatoms F, Cl, Br, I, O, or N possibly introduced as substituents on R are not separated by exactly one carbon atom from a heteroatom selected from the group consisting of N, O and S R ^8b in each case independently represents a hydrogen atom or C ₁ -C ₅ alkyl, X ¹ is carbonyl, thiocarbonyl, C = NR ^8c group, C = N-OR ^8c group, C = N-NO ₂ group, C = N-CN group or sulfonyl, R ^8c in each case independently represents a hydrogen atom, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkylcarbonyl, C ₁ -C ₅ alkyloxycarbonyl or C ₁ -C ₅ alkylsulfonyl, X ² represents an oxygen atom or an —NR ^8b group, X ³ is carbonyl, thiocarbonyl, C = NR ^8c group, C = N-OR ^8c group, C = N-NO ₂ group, C = N-CN group or sulfonyl, X ⁴ represents an oxygen atom or sulfur or an —NR ^8c group, R ¹ represents a fluorine, chlorine, bromine or iodine atom, a C ₁ -C ₃ alkyl or a C ₁ -C ₃ alkoxy group, where the hydrogen atoms of a C ₁ -C ₃ alkyl or a C ₁ -C ₃ alkoxy group may optionally be fully or partially replaced by fluorine atoms, or denotes C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, nitrile, nitro group or amino group, R ² represents a hydrogen atom or a halogen or C ₁ -C ₃ alkyl, R ³ represents a hydrogen atom or C ₁ -C ₃ alkyl, R ⁴ and R ⁵ independently represent a hydrogen atom, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, linear or branched C ₁ -C ₆ alkyl, the hydrogen atoms of which may optionally be fully or partially replaced by fluorine atoms and which optionally can be substituted with a C ₃ -C ₅ cycloalkyl, nitrile, hydroxy group, a C ₁ -C ₅ alkyloxy group, the hydrogen atoms of which can optionally be completely or partially replaced by fluorine atoms, an allyloxy group, a propargyloxy group, a benzyloxy group, a C ₁ -C ₅ alkylcarbonyloxy group C ₁ -C ₅ alkilo sikarboniloksigruppoy, carboxy-C ₁ -C ₅ alkyloxy, C ₁ -C ₅ alkyloxycarbonyl-C ₁ -C ₅ alkyloxy, mercapto, C ₁ -C ₅ alkilsulfanilom, C ₁ -C ₅ alkylsulfonyl, carboxy, C ₁ -C ₅ alkyloxycarbonyl, aminocarbonyl, C ₁ -C ₅ alkylaminocarbonyl, di- (C ₁ -C ₅ alkyl) aminocarbonyl, C ₃ -C ₆ cycloalkyleneiminocarbonyl, aminosulfonyl, C ₁ -C ₅ alkylaminosulfonyl, di- (C ₁ -C ₅ alkyl) aminosulfonyl, C _C3-C6 tsikloalkileniminosulfonilom, amino, C ₁ -C ₅ alkylamino, di- (C ₁ -C ₅ alkyl) amino, C ₁ -C ₅ alkylcarbonyl minogruppoy, C ₁ -C ₅ alkylsulfonylamino, N- (C ₁ -C ₅ alkylsulfonyl) -C ₁ -C ₅ alkylamino or C ₃ -C ₆ cycloalkylcarbonylamino, carboxy, aminocarbonyl, C ₁ -C ₅ alkylaminocarbonyl, C ₃ -C ₆ cycloalkylaminocarbonyl, di- (C ₁ -C ₅ alkyl) aminocarbonyl, C ₁ -C ₅ alkoxycarbonyl or C ₄ -C ₆ cycloalkyleneiminocarbonyl or are phenyl, heteroaryl, phenyl-C ₁ -C ₅ alkyl or heteroaryl-C ₁ -C ₅ alkyl which in the phenyl or heteroaryl moieties may optionally be one to three substituted with identical or different substituents selected from the group consisting of halogen atoms, C ₁ -C ₅ alkyl, di- (C ₁ -C ₅ alkyl) amino group, hydroxy group, C ₁ -C ₅ alkyloxy group, mono-, di- and trifluoromethoxy group, carboxy group and C ₁ -C ₅ alkyloxycarbonyl, or a 3-7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C ₁ -C ₅ alkyl or cycloalkyleneimino-C ₁ -C ₃ alkyl group, where in 4-7-membered rings in the cyclic part one methylene group may optionally be replaced in -N (R ^8c) -group, an oxygen or sulfur atom or a -S (O) - or -S (O) ₂ group or at 4-7-membered rings in the cyclic moiety two adjacent methylene groups together may optionally be replaced by ^{-C (O) N (R 8b} ) - or -S (O) ₂ N (R ^8b) -group or at 6-7-membered rings in the cyclic moiety three adjacent methylene groups may optionally be jointly replaced by substituted -OC (O) N (R ^8b ) -, -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) -group, provided that the above 3-7-membered cycloalkyl, cycloalkenylimino, cycloalkyl-C ₁ -C ₅ alkyl or cycloalkyleneimino-C ₁ -C ₃ alkyl group in which two heteroatoms from the group comprising oxygen and nitrogen are separated from each other each other with exactly one optionally substituted -CH ₂ group, wherein the above 3-7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C ₁ -C ₅ alkyl or cycloalkenimino-C ₁ -C ₃ alkyl group may be substituted one or two -CH ₂ groups respectively with one or two C ₁ -C ₃ alkyl groups, or R ⁴ and R ⁵ together with the carbon atom to which they are attached form C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl, where C ₃ -C ₈ cycloalkyl or C ₄ -C ₈ cycloalkenyl may be substituted individually carbon atom C ₂ -C ₅ alkylene or simultaneously can be replaced by two different carbon atoms C ₁ -C ₄ alkylene with the formation of the corresponding spirocyclic system, respectively, having an internal bridge of the bicyclic system, one of the methylene groups C ₄ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl, respectively, the above corresponding of the corresponding spirocyclic system, respectively, of the corresponding corresponding bicyclic system with an internal bridge indicated above, can be replaced by an oxygen or sulfur atom, an —N (R ^8c ) group, a carbonyl, sulfinyl or sulfonyl and / or two directly adjacent methylene groups of C ₄ -C ₈ cycloalkyl together can be replaced by a -C (O) N (R ^8b ) -, -C (O) O - or -S (O) ₂ N (R ^8b ) group and / or three directly adjacent C ₆ -C methylene groups ₈ cycloalkyls together can be replaced by -OC (O) N (R ^8b ) -, -N (R ^8b ) C (O) N (R ^8b ) - or -N (R ^8b ) S (O) ₂ N (R ^8b ) group, 1-3 carbon atoms C ₃ -C ₈ c icoalkyl, respectively, of the above corresponding spirocyclic system, respectively, of the above corresponding bicyclic system with an internal bridge, optionally independently from each other, can be substituted, respectively, by one or two fluorine atoms or one or two identical or different C ₁ -C ₅ alkyl, nitrile, hydroxy , C ₁ -C ₅ alkyloxy, C ₁ -C ₅ alkylcarbonyloxy, carboxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyloxycarbonyl-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkylsulfanyl, C ₁ - With ₅ alkylsulfonyl, car boxing, C ₁ -C ₅ alkyloxycarbonyl, aminocarbonyl, C ₁ -C ₅ alkylaminocarbonyl, di- (C ₁ -C ₅ alkyl) aminocarbonyl, C ₃ -C ₆ cycloalkyleneiminocarbonyl, aminosulfonyl, C ₁ -C ₅ alkylaminosulfonyl, di- ( C ₁ -C ₅ alkyl) aminosulfonyl, C ₃ -C ₆ cycloalkyleneiminosulfonyl, amino, C ₁ -C ₅ alkylamino, di- (C ₁ -C ₅ alkyl) amino, C ₁ -C ₅ alkylcarbonylamino, C ₁ -C ₅ alkylsulfonylamino, N- (C ₁ -C ₅ alkylsulfonyl) -C ₁ -C ₅ alkylamino or C ₃ -C ₆ cycloalkylcarbonylamino groups, 1 or 2 carbon atoms of C ₃ -C ₈ cycloalkenyl optional o independently of each other, can be substituted respectively with C ₁ -C ₅ alkyl, nitrile, carboxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyloxycarbonyl-C ₁ -C ₅ alkyl, carboxy, C ₁ -C ₅ alkyloxycarbonyl, aminocarbonyl, C ₁ -C ₅ alkylaminocarbonyl, di- (C ₁ -C ₅ alkyl) aminocarbonyl, C ₃ -C ₆ cycloalkyleneiminocarbonyl, aminosulfonyl, C ₁ -C ₅ alkylaminosulfonyl, di- (C ₁ -C ₅ alkyl) aminosulfonyl, C ₃ -C ₆ cycloalkyleneiminosulfonyl and 1 or 2 carbon atoms of C ₄ -C ₈ cycloalkenyl which are not double-linked to another carbon atom, yazatelno independently from each other be substituted by one or two fluorine atoms or hydroxy group, C ₁ -C ₅ alkyloxy, C ₁ -C ₅ alkylcarbonyloxy, C ₁ -C ₅ alkilsulfanilom, C ₁ -C ₅ alkylsulfonyl, amino, C ₁ -C ₅ alkylamino, di- (C ₁ -C ₅ alkyl) amino, C ₁ -C ₅ alkylcarbonylamino, C ₁ -C ₅ alkylsulfonylamino, N- (C ₁ -C ₅ alkylsulfonyl) -C ₁ -C ₅ alkylamino or C ₃ - C ₆ cycloalkylcarbonylamino group, provided that such formed jointly residues R ⁴ and R ^5, C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ n kloalkenilnaya group, respectively corresponding to the above spirocyclic system, respectively corresponding to the above bicyclic bridged system in which two ring heteroatoms from the group consisting of oxygen and nitrogen are separated by exactly one optionally substituted -CH ₂ group and / or wherein one or both methylene groups of the cycle, which is / are directly connected / coupled with the carbon atom to which they are attached residues R ⁴ and R ^5, replaced / are replaced by heteroatom from the group s, including oxygen, nitrogen and sulfur, and / or in which a substituent connected to the cyclic group, which is characterized in that the heteroatom from the group comprising oxygen, nitrogen, sulfur and a halogen atom, is directly connected to the cyclic group, is separated from another heteroatom from a group comprising oxygen, nitrogen and sulfur, with the exception of a sulfonic group, exactly one optionally substituted methylene group and / or in which two oxygen atoms are directly connected to each other and / or in which a heteroatom from the group comprising an acid genus, nitrogen and sulfur directly linked to a carbon atom which is connected by a double bond to another carbon atom and / or which contain one ring with three ring members, one or more of which represent an oxygen or sulfur atom or -N (R ^8c ) group are excluded from the scope of the invention, R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, nitrile, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy group, where the hydrogen atoms of C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy groups may optionally be completely or partially replaced by fluorine atoms, R ⁷ in each case independently denotes C ₁ -C ₃ alkyl, the hydrogen atoms of which may optionally be fully or partially replaced by fluorine atoms, or denotes a hydroxy group or C ₁ -C ₃ alkyloxy group, the hydrogen atoms of which may optionally be completely or partially replaced by fluorine atoms, or denotes an amino group, a C ₁ -C ₃ alkylamino group, a di- (C ₁ -C ₃ alkyl) amino group, a C ₃ -C ₆ cycloalkyleneimino group, a carboxy group, nitrile, C ₁ -C ₃ alkoxycarbonyl, aminocarbonyl, C ₁ -C ₃ alkylaminocarbonyl or di- (C ₁ -C ₃ alkyl) aminocarbonyl, however, the term “heteroaryl group” referred to in the definitions of substituents referred to above means, unless otherwise indicated, a monocyclic 5- or 6-membered heteroaryl group, which, if it is 6-membered, contains one, two or three nitrogen atoms, and if is 5-membered, or contains optionally substituted C ₁ -C ₃ alkyl, phenyl or phenyl-C ₁ -C ₃ alkyl imino group, an oxygen or sulfur atom, or contains optionally substituted C ₁ -C ₃ alkyl, phenyl, amino-C ₂ -C ₃ alkyl, C ₁ -C ₃ alkylamino-C ₂ -C ₃ alkyl, di- (C ₁ -C ₃ alkyl) a mino-C ₂ -C ₃ alkyl, C ₃ -C ₆ cycloalkylenimino-C ₁ -C ₃ alkyl or phenyl-C ₁ -C ₃ alkyl imino group or an oxygen or sulfur atom and optionally a nitrogen atom, or contains optionally substituted C ₁ - With ₃ alkyl or phenyl-C ₁ -C ₃ alkyl an imino group and two or three nitrogen atoms and can be substituted in the carbon skeleton with one or two R ⁷ residues and with which, optionally, substituted by an atom can also be condensed through two adjacent carbon atoms fluorine, chlorine or bromine atom or the residue R ⁷ and the phenyl ring which is further connected Th by a nitrogen atom or through a carbon atom of a heterocyclic moiety or a fused phenyl ring, the term “halogen atom” mentioned above in the definitions of substituents means, unless otherwise indicated, an atom from the group consisting of fluorine, chlorine, bromine and iodine mentioned above in the definitions of substituents alkyl, alkenyl, alkynyl and alkoxy groups containing more than two carbon atoms may, unless otherwise indicated, have a straight or branched chain, and alkyl groups in the above dialkylated residues, for example dialkylamino groups may be identical or different and the hydrogen atoms of the methyl substituents mentioned above in the definition of substituents of methyl or ethyl groups can be, unless otherwise indicated, completely or partially replaced by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. 2. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, characterized in that A represents the remainder of the General formula

,

,

,

,

,

,

, or

where m denotes the number 1 or 2, R ^8a in each case independently denotes a hydrogen or fluorine atom, C ₁ -C ₃ alkyl, hydroxy group, hydroxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl , amino group, C ₁ -C ₃ alkylamino group, di- (C ₁ -C ₃ alkyl) amino group, amino-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylamino-C ₁ -C ₃ alkyl or di- (C ₁ -C ₃ alkyl) amino-C ₁ -C ₃ alkyl, however, in the above substituted 5-7 membered residues A, the heteroatoms F, O or N optionally introduced as substituents R ^8a are not separated by exactly one carbon atom from a heteroatom selected from the group consisting of N, O and S, R ^8b represents a hydrogen atom or C ₁ -C ₃ alkyl, X ¹ is carbonyl, thiocarbonyl, C = NR ^8c group, C = N-OR ^8c group, C = N-CN group or sulfonyl, R ^8c represents a hydrogen atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkylcarbonyl or C ₁ -C ₄ alkyloxycarbonyl, X ² represents an oxygen atom or an —NR ^8b group, X ³ is carbonyl, thiocarbonyl, C = NR ^8c group, C = N-OR ^8c group, C = N-CN group or sulfonyl, X ⁴ represents an oxygen atom or an —NR ^8c group, R ¹ represents a chlorine or bromine atom, methyl, trifluoromethyl or methoxy group, R ² denotes a hydrogen atom or fluorine, R ³ represents a hydrogen atom, R ⁴ is methyl, which may optionally be substituted with a hydroxy group, methoxy group, benzyloxy group, methoxycarbonyl or pyridin-4-yl, 1-methylpyrazin-3-yl, phenyl, pyridin-3-yl or pyrazin-2-yl, R ⁵ represents a hydrogen atom or methyl or R ⁴ and R ⁵ together with the carbon atom to which they are attached form C ₃ -C ₆ cycloalkyl or C ₅ -C ₆ cycloalkenyl, where C ₅ -C ₆ cycloalkyl or C ₅ -C ₆ cycloalkenyl can be substituted simultaneously in two different carbon atoms C ₁ -C ₂ alkylene with the formation of a bicyclic system having an internal bridge, one of the methylene groups C ₄ -C _{6 of} dicloalkyl or C ₅ -C ₆ cycloalkenyl, respectively, of the above corresponding bicyclic system with an internal bridge can be replaced by an oxygen atom or -N (R ^8c) -group, provided that the similarity s formed jointly residues R ⁴ and R ^5, C ₃ -C ₆ cycloalkyl or C ₅ -C ₆ cycloalkenyl group, respectively corresponding to the above bicyclic bridged system in which one methylene group of the cycle, which is directly connected with the carbon atom to which are attached residues R ⁴ and R ⁵ is replaced by a heteroatom from the group consisting of oxygen and nitrogen, and / or the heteroatom of the group consisting of oxygen and nitrogen is directly connected to a carbon atom which is connected by a double bond to another atom IOM carbon, and / or which contain one ring with three ring members, one or more of which represent an oxygen atom or -N (R ^8c) -group, are excluded from the scope of the invention, R ⁶ represents a chlorine or bromine atom, however, the term “halogen atom” mentioned in the definitions of substituents means, unless otherwise indicated, an atom from the group consisting of fluorine, chlorine, bromine and iodine, the alkyl and alkoxy groups mentioned in the definitions of substituents containing more than two carbon atoms may, unless otherwise indicated, have a straight or branched chain, and the alkyl groups in the above dialkylated residues, for example dialkylamino groups, may be identical or different and the hydrogen atoms of the above metal substituents n or ethyl groups can be, unless otherwise indicated, completely or partially replaced by fluorine atoms, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts. 3. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, characterized in that R ⁴ and R ⁵ do not denote hydrogen. 4. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group. 5. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, characterized in that R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group, while in the cyclic group, respectively, in the corresponding bicyclic system with an internal bridge, respectively, in a spirocyclic system, according to the indicated conditions, one metal group is replaced by an oxygen atom or an N (R ^8c ) group. 6. The substituted thiophene-2-carboxamides of the general formula I according to claim 1, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclic group

or

. 7. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, in which R ⁴ and R ⁵ together with the carbon atom to which they are attached form a bicyclic system with an internal bridge

,

or

. 8. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, wherein residue A represents a group

or

. 9. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, wherein residue A represents a group

or

. 10. Substituted thiophene-2-carboxamides of the general formula I according to claim 1, wherein R ⁶ is a bromine atom. 11. Physiologically compatible salts of the compounds according to one of claims 1 to 10. 12. A drug containing a compound according to one of claims 1 to 10 or a physiologically compatible salt according to claim 11 and optionally one or more inert carriers and / or diluents. 13. The use of a compound according to one of claims 1 to 10 or a physiologically compatible salt according to claim 11 for the preparation of a medicament having an inhibitory effect on factor Xa and / or related serine proteases. 14. The method of producing a medicine according to claim 13, characterized in that the compound according to one of claims 1 to 10 or a physiologically compatible salt according to claim 11 is combined chemically with one or more inert carriers and / or diluents. 15. The method of producing compounds according to one of claims 1 to 10, characterized in that (a) a compound of the general formula

, in which A, R ¹ , R ² and R ³ have the meanings indicated in claim 1, are acylated by reaction with a compound of the general formula

, in which R ⁴ and R ⁵ are as defined in claim 1, Z ⁶ is a protecting group, Q is a hydroxy group, a C ₁ -C ₄ alkoxy group, an acyloxy group or a halogen atom, followed by cleavage of the protective group Z ⁶ to give a compound of the general formula

, wherein A, R ^1, R ^2, R ^3, R ^{4 and} R ⁵ are ^as defined in claim 1, and then the compound of general formula (XIX) is subjected to an acylation reaction with a compound of general formula

, in which R ⁶ has the meanings indicated in claim 1, a Q denotes a hydroxy group, a C ₁ -C ₄ alkoxy group, a halogen atom or an acyloxy group, to obtain a thiophene-2-carboxamide of the general formula (I), or (b) a compound of the general formula

, in which R ⁴ and R ⁵ have the meanings indicated in claim 1, a Z ⁹ denotes a protective group, subjected to acylation by interaction with a compound of the General formula

, in which R ⁶ has the meanings indicated in claim 1, and Q denotes a hydroxy group, a C ₁ -C ₄ alkoxy group, a halogen atom or an acyloxy group, followed by cleavage of the protective group Z ⁹ to obtain a compound of the general formula

, in which R ⁴ , R ⁵ and R ⁶ have the meanings indicated in claim 1, and Q denotes a hydroxy group, a C ₁ -C ₄ alkoxy group, a halogen atom or an acyloxy group, and then the compound of the general formula (XXII) is further acylated by reaction with the compound of the general formulas

, in which A, R ¹ , R ² and R ³ have the meanings indicated in claim 1, to obtain thiophene-2-carboxamide of the general formula (I), or (c) a compound of the general formula

, in which A, R ¹ , R ² and R ³ have the meanings indicated in claim 1, are acylated by reaction with a reactive derivative of a carboxylic acid of the general formula

, in which R ⁴ -R ⁶ have the meanings indicated in claim 1, to obtain thiophene-2-carboxamide of the general formula (I).